Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.

Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.

Glutamine metabolism targeting liposomes for synergistic chemosensitization and starvation therapy in ovarian cancer.

Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

pH-activated nanoplatform for visualized photodynamic and ferroptosis synergistic therapy of tumors.

To overcome drug resistance and improve precision theranostics for hepatocellular carcinoma (HCC), a nanoplatform with an "off/on" function for multimodality imaging (near-infrared-II (NIR-II) fluorescence imaging, magnetic resonance imaging (MRI), and photoacoustic imaging) and synergistic therapy (photodynamic therapy and ferroptosis) activated by an acidic pH in the tumor microenvironment is proposed. Although many photosensitizers with photodynamic effects have been reported, very few of them have outstanding photodynamic effect and high stability with response to endogenous stimuli capable of NIR-II imaging. Herein, a new amphiphilic photosensitizer SR780 derived from croconaine dye, was developed with satisfactory photodynamic effects and pH-responsive NIR-II imaging. Interestingly, it was deactivated by coordination with Fe3+ (SR780@Fe) and activated during their release under mild acidic condition. Ferroptosis can generate hydroxyl free radical and lipid peroxide, which aggravate the oxidative stress of tumor cells and mediate their death while depleting glutathione (GSH) to enhance photodynamic effect. In situ pH-activatable theranostic nanoplatform, SR780@Fe-PAE-GP, was thus developed by loading SR780@Fe with pH-responsive polymers, modified by a glypican-3 (GPC-3) receptor-targeting peptide. The synergistic antitumor effects were confirmed both in vitro and in vivo, and the tumor inhibition rate of the SR780@Fe-PAE-GP + L treatment group reached 98%.